The presence of certain diseases appears to correlate with expression of a mutant allele. For example, amyloidosis can be correlated to certain transthyretin (TTR) mutations. In such cases, it is desirable to selectively silence expression of the mutant allele, while maintaining expression of the wild-type variant.
Amyloidosis related to transthyretin (ATTR) involves the depositing of amyloid fibril proteins in various organs and tissues, including the peripheral, autonomic, and central nervous systems. Transthyretin (TTR) is a secreted thyroid hormone-binding protein that binds and transports retinol binding protein, and serum thyroxine in plasma and cerebrospinal fluid.
The pathology of ATTR may include many TTR mutations. Symptoms of ATTR often include neuropathy and/or cardiomyopathy. Peripheral neuropathy can begin in the lower extremities, with sensory and motor neuropathy, and can progress to the upper extremities. Autonomic neuropathy can be manifest by gastrointestinal symptoms and orthostatic hypotension.
Patients with TTR gene Val-30-Met, the most common mutation, have normal echocardiograms. However, they may have conduction system irregularities and need a pacemaker. The ATTR V30M variant can cause lower extremity weakness, pain, and impaired sensation, as well as autonomic dysfunction. Vitreous and opaque amyloid deposits can be characteristic of ATTR.
Survival upon onset of ATTR may be from five to fifteen years. The major treatment for ATTR amyloidosis is liver transplantation, which removes the major source of variant TTR production and replaces it with normal TTR. Liver transplantation slows disease progression and some improvement in autonomic and peripheral neuropathy can occur.
There is currently no pharmacological therapy that can undo the formation of TTR amyloid.
There is a continuing need for therapeutics for ATTR and other amyloid-related diseases.
There is a long-standing need for gene silencing agents that can selectively downregulate a disease-related allele.
There is also a need for active agents that can provide efficient and specific knockdown of TTR.